Head and neck cancers (HNC) impose a significant biomedical burden by accounting for over 8000 deaths and 40,000 new cases each year. HNC patients often will require multimodality treatment with surgery, radiation, and chemotherapy. Although radiotherapy has increased survival it also results in damage to adjacent normal tissues leading to significant morbidity. The corrosive impact of these radiation induced side effects can be unrelenting and their complex management is rarely remedial. Severely problematic wound healing issues impact the reconstructive efforts to replace the bone and soft tissue removed by tumor extirpation as well as the options to treat radiation induced pathologic fractures and osteoradionecrosis. Standard of care currently dictates mandibular reconstruction utilizing free tissue transfer from other parts of the body. These complex operations entail extended hospitalizations and their complications often lead to delays in initiation of therapy jeopardizing prognosis as well as quality of life. Advances in biotechnology have afforded a unique opportunity to combine knowledge from both basic and clinical investigation to innovate new treatment regimens for radiation induced side effects by bringing novel and more effective therapeutic strategies into clinical settings. The utilization of Distraction Osteogenesis (DO) for tissue replacement after oncologic resection could have immense potential therapeutic ramifications. DO, the creation of new bone by the gradual separation of two osteogenic fronts, generates an anatomical and functional replacement of deficient tissue from local substrate. Radiation drastically impairs bone healing, precluding the utilization of DO as a durable and predictable reconstructive method for HNC. The central hypothesis to be tested in this proposal is that the deleterious effects of radiation on bone formation can be mitigated to allow both functional restoration and successful regeneration of the mandible as well as restore the capacity for normal bone healing. Recent work in our laboratory demonstrated specific metrics of diminished bone quality within healing fractures and distracted regions of irradiated mandibles. We then employed a series of pharmacologic and tissue engineering strategies to assuage the adverse impact of radiation induced injury in order to optimize reconstruction and repair. Each of our therapies demonstrated partial remediation of the radiation induced degradation of bone healing. The consequential finding of these experiments was the ability to generate a bony union in scenarios where this was not previously possible. Although, the key metrics of bone healing were significantly enhanced, they were not completely restored and therefore not yet optimized for translation to the clinical arena. The current proposal entails combining our efficacious individual treatment regimens into a carefully designed plan engineered to maximize therapeutic synergies to achieve a more robust and predictable reconstruction. The long term goal of this proposal is to provide fundamental information that can be translated from the bench to the bedside to lead to improved treatment modalities to this severely compromised patient population.